Abstract
The p.Thr1406Asn (rs1047891) polymorphism of the carbamoyl-phosphate synthetase 1 (CPS1) gene has been linked to functional consequences affecting the downstream availability of the nitric oxide precursor L-arginine. L-arginine concentrations are decreased in preterm infants with necrotizing enterocolitis (NEC). In this multicenter prospective study, we investigated the association of the p.Thr1406Asn polymorphism with NEC in 477 preterm infants (36 cases of NEC) from 4 European neonatal intensive care units (Maastricht, Las Palmas de Gran Canaria, Mantova, and Milan). Allele and genotype frequencies of the p.Thr1406Asn polymorphism did not significantly differ between the infants with and without NEC. In contrast, the minor A-allele was significantly less frequent in the group of 64 infants with the combined outcome NEC or death before 34 weeks of corrected gestational age than in the infants without the outcome (0.20 vs. 0.31, P = 0.03). In addition, a significant negative association of the A-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.54, 95% CI 0.29–0.99) and the additive (aOR 0.58, 95% CI 0.36–0.93) genetic models. In conclusion, our study provides further evidence that a functional variant of the CPS1 gene may contribute to NEC susceptibility.
Highlights
IntroductionA number of functional single nucleotide polymorphisms (SNPs) have been identified in the CPS1 gene[22,23,24]
We report the results of such study, involving 477 preterm infants (36 cases of Necrotizing enterocolitis (NEC)) from four neonatal intensive care units located in three different European countries (Spain, Italy, and the Netherlands)
Infants with NEC showed a higher incidence of vaginal delivery, mechanical ventilation, Bronchopulmonary dysplasia (BPD), hypotension, Intraventricular hemorrhage (IVH), PVL, Patent ductus arteriosus (PDA), Retinopathy of prematurity (ROP) and mortality
Summary
A number of functional single nucleotide polymorphisms (SNPs) have been identified in the CPS1 gene[22,23,24] One of those SNPs (p.Thr1406Asn published as T1405N; rs1047891 formerly designated as rs7422339) has been linked to functional consequences affecting the downstream availability of urea-cycle intermediates, including L-arginine[22,23,24]. We reported in a retrospective series of 17 preterm infants with NEC and 34 controls that patients with NEC showed an underrepresentation of the A-encoded variant of the p.Thr1406Asn polymorphism of CPS1 27 Those results suggested that the A-allele conferred protection against NEC and warranted confirmation using a prospective design and larger sample size. Since death in the first weeks of life is a competing outcome for NEC, we analyzed the association of the p.Thr1406Asn polymorphism with the combined outcome NEC or death before 34 weeks of corrected gestational age(GA)
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